Field of the Invention
The invention related to peptides for the inhibition of IGF-1 activity.
Background Information
Carcinogenesis is commonly related to the loss of cell quiescence and the abrogation of cell division control, provoking uncontrolled cell proliferation and biomass increase. Proliferation is a complex process, but a key element is overexpression of growth factors and/or their receptors in the cell (Moyse et al. 1985, Cassoni et al. 2006, Hanahan et al. 2000). Normally, these protein pathways, collectively termed ‘signal transduction’, are tightly controlled. Deregulation of signaling pathway gives rise to the progression of oncogenic transformation and tumorigenesis. All cancer cells exhibit a deregulated cell cycle, leading to the evolution of cells which can evade cancer therapies. Many factors acting as a network are involved in cell cycle progression and cell proliferation. In particular, growth factors are capable of stimulating entry into S phase of the cell cycle and therefore, cell division.
Among those, Insulin-like growth factors (IGFs) are important mediators of growth, development, and survival. They are synthesized by almost any tissue in the body. The action of IGFs is modulated by a complex network of molecules, including binding proteins, proteases and receptors, which all comprise the “IGF system”.
IGF-1, among others, which synthesis is activated by GH, acts as an endocrine hormone and could be considered as the actual growth hormone (Laron, 2001). The effect of IGF-1 can also be mediated by paracrine/autocrine mechanism. In children, IGF-1 stimulates growth whereas in adults, it increases anabolism. IGF-1 is a peptide that binds IGF-1 receptor (IGF-1R), a membrane receptor expressed in various tissues, e.g. liver, kidney, lung, muscles, bone, nervous and cartilaginous tissues. Activation of IGFR-1 by IGF-1 is implicated in cell survival, growth, proliferation, differentiation, and migration in epithelial and mesenchymal tissues (Perona, 2006). The activation of the IGF-1 receptor by suitable ligand plays a central role in the proliferation of most cell types. Evidence from in vitro and animal studies suggests that overexpression of IGF-1 by cancer cells and/or the nearby stroma as well as the IGF-1 receptors by the cancer cells plays a significant role in establishing a transformed phenotype in an increasing number of malignancies. More specifically, IGF-1 promotes protein synthesis and inhibition of apoptosis (programmed cell death) (Yanochko et al 2006, Colon et al 2007, Inoue et al 2005).
The role of IGF-1 signaling network in carcinogenesis and tumor progression, including metastatic processes, is established (Hofmann et al 2005). In addition, a growing number of epidemiologic studies suggest that increased serum levels of IGF-1 and/or altered expression of their receptors are associated with increased risk for developing cancer (Vella et al 2001, Talapatra et al 2001, Kucab et al 2003, Kambhampati et al 2005, Bjorndahl et al 2005, Gennigens et al 2006, Velcheti et al 2006, Sisci et al 2007, Samani et al 2007). The critical role of IGF-1/GH axis in oncogenesis and stimulation of tumor progression is suggested in various studies, particularly in a recent study describing an IGF-1 congenital deficiency that could prevent from cancer development (Sheva et al 2007).
These data indicate that IGF dysregulation should now be considered as a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups. Accordingly, clinical studies have been carried out on inhibitors of IGF-1 activities and indicate potential interest of their use in various type of cancer (Min et al 2005, Camirand et al 2005, Chinnavian et al 2006, Wu et al 2006, Deutsh et al 2005, Warshamana-Greene et al 2005). Since IGF-1 is the principal mediator of GH, IGF-1 production can be decreased or inhibited upstream GH production, with Somatostatin for example.
Somatostatin (Somatotrope Release Inhibiting Factor or SRIF) was known for its effect of inhibiting GH secretion. Indeed, somatostatin is a growth hormone-releasing hormone (GHRH) antagonist. Somatostatin and GHRH are both secreted by hypothalamic neurons and controlled GH secretion. SRIF has an indirect effect on IGF-1 synthesis by inhibiting GH. SRIF also has a peripheral action: it has been shown to inhibit gastro-intestinal and pancreatic hormones secretion.
Several therapeutic protocols use the SRIF and synthetic analogs capacity to inhibit cell proliferation and cell death induction to treat different types of cancer. Moreover, SRIF can inhibit angiogenesis mediated by Vascular Endothelial Growth Factor (VEGF), thus representing a potential clinical interest for the control of tumor growth (Ferjoux et al 2000, Dasgupta 2004, Garcia de la Torre et al. 2002).
However, SRIF analogs are useful in treatment of tumor expressing SRIF receptors only. SRIF receptors have been identified in a variety of human tumors and cancer etiology is associated with an alteration in SRIF receptor expression pattern in many instances. Efficiency of SRIF analogs has already been assessed for neuroendocrinic, gastroenteropancreatic, brain, breast, prostatic and lung tumors treatment (Ferjoux et al 2000). Besides, one should bear in mind that SRIF receptors levels and expression pattern greatly differ from one carcinoma to another.
Different somatostatin analogs useful as “IGFs system” inhibitors have been proposed (Pawlikowski M. et al., 2004), namely BIM 23A387, octreotide or lanreotide. These molecules allow effective modulation of receptors or ligand expression and could be considered as new candidate drugs for cancer and acromegaly treatments. Other example is bispecific ligand BIM-23244, which is able to suppress GH secretion in somatotropic adenoma (Rani C., 2004, Rani C., 2006, Pandit A., 2008).
International patent application WO03/048206 discloses chimeric peptides that potentiate GH activity and their use for stimulating cell proliferation.